Rheumatoid arthritis (RA) affects approximately 1.3 million adults in the United States and up to 1.5% of the population worldwide. In its progressive form the disease has debilitating effects including painful inflammation and destruction of the joints. This affliction leads to considerable lost work and disability. A hallmark of the RA inflammatory response is vascular instability. The vascular endothelium is continuously balancing the requirement to maintain a stable network with a capacity to regenerate. It is continuously challenged by destabilizing factors in response to inflammatory stress. An increase in vascular permeability in RA leads to infiltration of the synovial endothelium by leukocytes. Indeed, this may be a critical first step in initiation of RA, as well a its progression. We have shown that inhibition of a non-canonical ARNO/Arf6 pathway, independent of the canonical NF-kB pathway and immune system regulation is involved in maintaining vascular stability and provides consistent therapeutic benefit in a mouse model of RA. Current therapeutics for RA fall into a number of categories: cytokine inhibitors, B cell and T cel depleting or blocking agents, inhibitors of purine and pyrimidine synthesis, NSAIDs, and corticosteroids. While their direct mechanisms of action are varied, the central strategy of these therapies is to dampen the immune response via inhibition of the NF-kB pathway. The dominant market players are costly anti-TNF injectable therapies that carry a considerable risk of increased infection. The goal of this project is to identify clinically and commercially viable structural classes of ARNO/Arf6 small molecule inhibitors that may be effective at preventing the advancement of RA. At completion of this Phase I grant, we will have identified a series of structural classes and hit compounds that reduce endothelial permeability. In Phase II our efforts will focus on optimizing hit compounds for solubility, permeability, metabolic stability, and specificity, while minimizing potential safety concerns. The resulting lead compounds must be novel chemical entities that can be patent protected. Following this optimization step, lead compounds will be tested in in vivo RA models, and their pharmacokinetic, ADME, and safety profiles will be established. By the end of Phase II, we will have a set of prioritized leads and will be well-positioned to begin IND-enabling preclinical studies.